In recent years, the development of a drug delivery system (DDS) which maximizes the drug effect and minimizes the side effects has been sought. DDS can be classified according to morphology and methods of administration as follows.
1) A system in which a drug is complexed to a polymeric membrane or formed as a molded product and is adhered on skin or a mucous membrane for slow release or absorption of the drug through the skin or the mucous membrane, respectively. PA1 2) A body implant system in which a drug complexed to various forms of matrix is left in an organ or subcutaneous tissues for slow release. PA1 3) A system in which a drug microencapsulated by means of liposome or lipid microspheres or a prodrug formed by covalently bonding a drug to a polymeric compound is administered directly in blood or tissues. PA1 1) Enhancement of ease of use of a drug by improvement of the chemical and biological properties. PA1 2) Increasing the stability of the products in the body, such as in blood or tissues.
As an example the body implant system described in #2 above, an anti-cancer agent is complexed to a polymeric carrier. The implant is applied to the cancerous host and the anti-cancer agent is released continuously. The implant has been developed to reduce the size of tumor, extend the life and relieve pain caused by the cancer. This system has been applied to drugs other than anti-cancer agents, for example anesthetics, narcotic antagonists, immunoactivators such as interleukin, and interferons, and various hormones. In body implants, a drug is dispersed in polymeric matrix mainly by physical means, and allowed to diffuse from the interior of the matrix to carry out a slow release. Because certain drugs can be readily complexed to the matrix, the technology is applicable to a broad range of drugs. Another advantage of the system is that there is very little loss of activity of the drug during the manufacturing process.
The clinical application of these body implants requires implantation by a surgical means in a form suitable for its application, such as needles, rods, films or pellets. The polymeric matrix can include polymers which do or do not degrade in the body. In the case of a matrix which does not decompose in the body, the implant has to be extracted by surgical method after releasing the drug contained therein. Thus, the implants that must be removed surgically are not desirable for clinical application because of pain, infection, and scar formation that might be imposed on the patient.
Additionally, the action of the drug being released from an implant left in the body tends to be limited to the region in contact with the implant. Therefore, distribution of the drug in the focus region tends to be nonuniform.
Further, an implant embedded in the body may act as an antigen. The implant may be recognized by the body as a foreign substance, and a capsulation consisting of the tissue components is formed around the implant as a defense mechanism. As a result, the efficiency of delivery of the drug to the focus is reduced further. Thus, the body implant system has numerous problems.
Drugs microencapsulated in liposome or lipid microspheres as described in #3 above are being developed in an effort to overcome the problems associated with body implants. Microencapsulated drugs can be administered directly into blood or tissues without requiring surgical treatment. Certain products of this type are being developed and used clinically. Examples are oil-soluble drugs such as steroids, indomethacin, prostaglandin and so on, mixed into lipid microspheres, and water-soluble anti-cancer drugs such as adriamycin or mitomycin or water-soluble hormones such as insulin, microencapsulated in a liposome.
The lipid microsphere is a droplet of soybean oil, coated with a monolayer film of lecithin. Therefore, this application is only useful for drugs which are soluble in soybean oil, and not useful for water-soluble drugs. Also, because lipid microspheres are prepared by suspending soybean oil and lecithin in water, particle size is large and uneven, and thus it is difficult for the product to be distributed uniformly and broadly when it is injected into tissue. Further, the drug being incorporated in lipid microspheres is released by a diffusion process through the oil droplet. Thus, the rate of release decreases in exponential manner, and continuous release at a constant rate is difficult.
Similar to the situation with lipid microspheres, it is difficult to manufacture liposome products with a uniform particle size and to achieve a uniform or broad distribution of the drug when injected in the tissues. Also, there are problems with stability during storage and mechanical strength of the product, making it difficult to maintain the slow-releasing property of the drug for a lengthy period of time.
Accordingly, prodrugs, i.e., drugs that are chemically linked to a polymer, via covalent bonds in particular, have been developed in recent years. This technology has attempted to achieve the following goals.
Specifically, a drug with low solubility is made more soluble in water by linking to a water-soluble polymer such as dextran or poly-N-(2-hydroxy-propyl) methacrylamide and so on, to facilitate its delivery. Or, by conversion of a drug into a polymer, its excretion from liver and kidney has been suppressed and its retention time in blood or in tissue has been extended. In this case, drug effect is expressed by release of the drug from the polymer by hydrolysis and the rate of slow release is controlled by the rate of hydrolysis.
Water-soluble prodrugs, unlike body implants, can be delivered uniformly into the blood or tissues by a simple method such as injection. However, due to the water soluble nature of the prodrug, after being injected into the body, it has a significantly faster rate of disappearance from the blood or tissues than the body implant or the microencapsulated drug. It is also known that the drugs covalently bonded to water-soluble polymers have a significantly faster rate of hydrolysis than drugs bonded to water-insoluble polymers.
Although prodrugs covalently bonded to water-soluble polymers have an advantageous way of administration, it is difficult to maintain a slow-releasing property for a lengthy period of time. On the other hand, water-insoluble prodrugs are advantageous from the standpoint of slow-releasing properties, but present difficulty in delivery of the drugs.
To date, a drug carrier that is easy to administer and can fully satisfy the requirement for slow release of the drug has not been provided. The objective of this invention is to provide a drug carrier that can be administered easily and can maintain a uniform concentration for a long period of time in the tissues.